Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors:: functional receptor-binding and in vivo electrophysiological studies

Background: Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors. Materials and methods: This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties. Results: Aripiprazole produced increases in [S-35]GTP gamma S binding to rat hippocampal membranes. Its potency (pEC(50)=7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT1A-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT1A-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT1A receptors (K (i)=4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT2A receptors (K (i)=3.4 nM), moderate affinity to 5-HT2C (K (i)=15 nM) and 5-HT7 (K (i)=39 nM) receptors, and low affinity to 5-HT6 receptors (K (i)=214 nM) and 5-HT transporter (K (i)=98 nM). In addition, aripiprazole potently blocked 5-HT2A-receptor-mediated increases in intracellular Ca2+ levels in a rat pituitary cell line (IC50=11 nM). Discussion: These results support a partial agonist activity for aripiprazole at 5-HT1A receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.